Rickets and Osteomalacia in the Glasgow Pakistani Community, 1961-71

The prevalence of vitamin D deficiency was reassessed in April and May 1971, 10 years after the discovery of widespread late rickets and osteomalacia in the Glasgow Pakistani community. Evidence of vitamin D deficiency was found in 28 out of 115 adults and children examined (24%). Children at the age of puberty were most severely affected by rickets, whereas most infants and younger children in the survey were protected by vitamin D supplements. Mild biochemical osteomalacia was common in Pakistani women.A total of 21 Pakistani and Indian children with rickets were admitted to Glasgow hospitals during 1968-70. These comprised 10 children with infantile rickets and 11 with late rickets. Four of the latter group required osteotomy for severe rachitic deformity.Late rickets and osteomalacia in Pakistani and Indian immigrants are not primarily due to nutritional deficiency of vitamin D, though the high phytate content of their diet may be of aetiological importance. A combination of environmental, social, and endogenous factors, the relative importance of which is not at present clear, may also be involved. Advice on the prophylaxis of vitamin D deficiency should be given to all Pakistani and Indian communities in the United Kingdom.     

Genome-wide association study of genetic determinants of LDL-c response to atorvastatin therapy: importance of Lp(a)

We carried out a genome-wide association study (GWAS) of LDL-c response to statin using data from participants in the Collaborative Atorvastatin Diabetes Study (CARDS; n = 1,156), the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT; n = 895), and the observational phase of ASCOT (n = 651), all of whom were prescribed atorvastatin 10 mg. Following genome-wide imputation, we combined data from the three studies in a meta-analysis. We found associations of LDL-c response to atorvastatin that reached genome-wide significance at rs10455872 (P = 6.13 × 10(-9)) within the LPA gene and at two single nucleotide polymorphisms (SNP) within the APOE region (rs445925; P = 2.22 × 10(-16) and rs4420638; P = 1.01 × 10(-11)) that are proxies for the ε2 and ε4 variants, respectively, in APOE. The novel association with the LPA SNP was replicated in the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) trial (P = 0.009). Using CARDS data, we further showed that atorvastatin therapy did not alter lipoprotein(a) [Lp(a)] and that Lp(a) levels accounted for all of the associations of SNPs in the LPA gene and the apparent LDL-c response levels. However, statin therapy had a similar effect in reducing cardiovascular disease (CVD) in patients in the top quartile for serum Lp(a) levels (HR = 0.60) compared with those in the lower three quartiles (HR = 0.66; P = 0.8 for interaction). The data emphasize that high Lp(a) levels affect the measurement of LDL-c and the clinical estimation of LDL-c response. Therefore, an apparently lower LDL-c response to statin therapy may indicate a need for measurement of Lp(a). However, statin therapy seems beneficial even in those with high Lp(a).     

Temporal and intrapopulation variation in prey choice of wintering geese determined by stable isotope analysis

1. Individual variability in prey preferences can have marked effects on many demographic parameters from individual survival and fecundity to the vital rates of entire populations. A population level response is ultimately determined by individual prey choices; however, the effect of individual dietary choice is often overlooked. 2. We determined prey choice by individual consumers, light-bellied Brent geese Branta bernicla, during the overwintering period. Two hundred and eighty-one individuals were sampled at distinct temporal points over two winters. Stable isotopic ratios of carbon and nitrogen for blood cells and blood plasma, from each sampled individual were measured. Isotopic ratios for potential prey items were also measured. 3. Delta15N and delta13C for blood samples were both significantly different between sample months. Generally we found a decrease in both isotopic ratios during the course of the winter. All potential prey items were also isotopically distinct. Multisource mixing models (isosource) were used to determine the range of possible contribution to the diet of individuals. 4. During early winter, diet consisted almost exclusively of sea grass Zostera spp. The level of Zostera spp. in the diet dropped until mid-winter, and was supplemented by the utilization of green algae Ulva lactuca, and Enteromorpha spp., and terrestrial grasses. Terrestrial grass comprised an increasing proportion of the diet in late winter, representing virtually the exclusive food source by April. 5. By examining intrapopulation variability in resource utilization we highlight a number of ecologically important factors not addressed by previous population level studies.     

Pollen-based reconstructions of biome distributions for Australia, Southeast Asia and the Pacific (SEAPAC region) at 0, 6000 and 18,000 14C yr BP

Aim This paper documents reconstructions of the vegetation patterns in Australia, Southeast Asia and the Pacific (SEAPAC region) in the mid‐Holocene and at the last glacial maximum (LGM). Methods Vegetation patterns were reconstructed from pollen data using an objective biomization scheme based on plant functional types. The biomization scheme was first tested using 535 modern pollen samples from 377 sites, and then applied unchanged to fossil pollen samples dating to 6000 ± 500 or 18,000 ± 1000 ¹⁴C yr bp . Results 1. Tests using surface pollen sample sites showed that the biomization scheme is capable of reproducing the modern broad‐scale patterns of vegetation distribution. The north–south gradient in temperature, reflected in transitions from cool evergreen needleleaf forest in the extreme south through temperate rain forest or wet sclerophyll forest (WSFW) and into tropical forests, is well reconstructed. The transitions from xerophytic through sclerophyll woodlands and open forests to closed‐canopy forests, which reflect the gradient in plant available moisture from the continental interior towards the coast, are reconstructed with less geographical precision but nevertheless the broad‐scale pattern emerges. 2. Differences between the modern and mid‐Holocene vegetation patterns in mainland Australia are comparatively small and reflect changes in moisture availability rather than temperature. In south‐eastern Australia some sites show a shift towards more moisture‐stressed vegetation in the mid‐Holocene with xerophytic woods/scrub and temperate sclerophyll woodland and shrubland at sites characterized today by WSFW or warm‐temperate rain forest (WTRF). However, sites in the Snowy Mountains, on the Southern Tablelands and east of the Great Dividing Range have more moisture‐demanding vegetation in the mid‐Holocene than today. South‐western Australia was slightly drier than today. The single site in north‐western Australia also shows conditions drier than today in the mid‐Holocene. Changes in the tropics are also comparatively small, but the presence of WTRF and tropical deciduous broadleaf forest and woodland in the mid‐Holocene, in sites occupied today by cool‐temperate rain forest, indicate warmer conditions. 3. Expansion of xerophytic vegetation in the south and tropical deciduous broadleaf forest and woodland in the north indicate drier conditions across mainland Australia at the LGM. None of these changes are informative about the degree of cooling. However the evidence from the tropics, showing lowering of the treeline and forest belts, indicates that conditions were between 1 and 9 °C (depending on elevation) colder. The encroachment of tropical deciduous broadleaf forest and woodland into lowland evergreen broadleaf forest implies greater aridity. Main conclusions This study provides the first continental‐scale reconstruction of mid‐Holocene and LGM vegetation patterns from Australia, Southeast Asia and the Pacific (SEAPAC region) using an objective biomization scheme. These data will provide a benchmark for evaluation of palaeoclimate simulations within the framework of the Palaeoclimate Modelling Intercomparison Project.     

Biochemical Response of Late Rickets and Osteomalacia to a Chupatty-free Diet

Eight Pakistani children with late rickets and two Pakistani women with osteomalacia were given a chupatty-free diet for seven weeks, substituting leavened bread of lower extraction. On this diet serum calcium levels rose to normal or near normal, levels of serum inorganic phosphorus rose slightly but significantly, and serum alkaline phosphatase levels showed a definite rise indicative of healing bone disease. It is concluded that the high phytate content of unleavened bread is the major cause of late rickets and osteomalacia in Pakistani and Indian communities in the United Kingdom. The simplest prophylactic measure seems to be the additional fortification with calcium carbonate of the high extraction flour used in preparing unleavened bread.     

Carrier-mediated inhibition of choline acetyltransferase

Incubation of rat forebrain synaptosomes with choline mustard aziridinium ion in a sodium-rich medium caused a time-dependent inhibition of the high-affinity transport of choline, as well as a significant decrease in intrasynaptosomal choline acetyltransferase activity. In the absence of added sodium choline uptake by a sodium-independent mechanism was also blocked in a time-dependent manner but intrasynaptosomal choline acetyl-transferase activity was unaltered. Neither monoethylcholine nor hemicholinium-3 changed intrasynaptosomal choline acetyl-transferase activity but competitively inhibited the transport of choline. The results indicate that there may be a fraction of choline acetyltransferase that is closely associated with the sodium-dependent high-affinity choline transport system and that this fraction can be irreversibly inhibited by choline mustard aziridinium ion, perhaps indirectly mediated by alkylation of the carrier.     

Novel 4-anilinoquinazolines with C-6 carbon-linked side chains: synthesis and structure-activity relationship of a series of potent, orally active, EGF receptor tyrosine kinase inhibitors

The structure-activity relationship of a novel subseries of 4-anilinoquinazoline EGFR inhibitors substituted at the C-6 position with carbon-linked side chains has been investigated. This exploration has led to the discovery of novel aminomethyl carboxamides with good biological, pharmacokinetic and physical properties.